In terms of symptoms and health trajectories associated with the menopausal transition (MT), there is what can be considered a conundrum. This refers to the observation that several deficits and poor health outcomes are related to the menopausal transition and generally resolved by hormone replacement therapy (HRT) but there are no direct causal links or empirical evidence for either the cause or justification of the current intervention therapies. Cognitive and memory loss (as well as many other symptoms) in mid-women is temporally related to declining ovarian function and can be retained by estrogen replacement however, a clear or significant decline in circulating estrogen has not been demonstrated to indicate a deficiency of estradiol at the time of symptom onset. In addition, several reports show that higher endogenous dehydroepiandrosterone (DHEA) safeguards against memory/cognitive loss but an equal number of studies in which DHEA intervention with exogenous DHEA results in no positive effect. In addition, there is no evidence to explain the woman-to-woman difference in symptoms in terms of a difference in a decline of ovarian function that predicts memory/cognitive declines. While women age quite differently . . . they all go through a near-identical change in ovarian function.
So, simply stated: What is it that identifies women who sufferer losses/symptoms from those that do not? To answer this question a large, longitudinal, multicenter clinical study has been carried out. The functional descriptor here is longitudinal because all previous studies were cross-sectional and, as is now understood, the basis for the expression of individual phenotypes during the MT can be recognized only when the same woman is evaluated serially for several years. (Crawford et al., 2009).
Cognitive loss is common among older Americans, approximately twenty percent of the U.S. population is over 60 years of age and this proportion is growing rapidly. The current female:male ratio is 1.3:1 therefore the number of affected women will rise proportionately. Memory and administrative function loss in women is a growing public concern and is a current national health issue. Women are at twice the risk of men for dementia when adjusted for chronologic age (Ott S L, The New York high-risk project: social and general intelligence in children at risk for schizophrenia. Schizophr Res. 1998; 31:1-11; Di Carlo A, Incidence of dementia, alzheimer's disease, and vascular dementia in Italy. The ILSA study. J Am Geriatr Soc. 2002; 50:41-48) and dementia is associated with a large number of other maladies particularly during the menopausal transition. Thus understanding the pathogenesis of cognitive function in mid-aged women has widespread implications for attenuation and prevention of national disease burden. Interventions to prevent memory disorders in women have two historic patterns. One is to follow the observation that hormone replacement therapy (HRT) ameliorates cognitive and administrative function loss, with the conclusion that “estrogen replacement” is therapeutic for maintaining neural function in mid-aged women despite the fact that there is no direct evidence that reduced endogenous estrogen levels are related to the pathogenesis of such cognitive disorders (Goldstein J M, Normal sexual dimorphism of the adult human brain assessed by in-vivo magnetic resonance imaging. Cereb Cortex. 2001; 11(6):490-497; Tobet S A, Hanna I K. Ontogeny of sex differences in the mammalian hypothalamus and preoptic area. Cell Mol Neurobiol. 1997; 17(6):565-601). The second logic is based on observation that higher endogenous circulating dehydroepiandrosterone (DHEA) levels are associated with less cognitive and administrative function loss in mid-aged women (Davis S R, 2008 Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 93:801-808; Haren M T, 2007 Lower serum DHEAS levels are associated with a higher degree of physical disability and depressive symptoms in middle-aged to older African American women. Maturitas 57:347-360) despite the fact that interventions with DHEA have had mixed, at best, results (Barad D, 2007 Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet 24:629-634; Kritz-Silverstein D, 2008 Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 56:1292-1298). Neither approach is completely effective, based on good science nor deemed to be entirely safe from unwanted somatic side effects.
Despite lacking clinical support, the intervention with estrogen treatment is currently the prevailing therapy for preserving cognitive function in mid-aged women and the risks are considered to out weigh the risks. The overriding question is, does an appropriate replacement therapy that maintains estrogen receptor signal transduction “tone” need to be a pure mitogenic estrogen such as estradiol that carries with it unwanted risks of inducing hyperplastic disease in estrogen-sensitive somatic tissues? Recent observations now indicate this is not true.
ERα in the hippocampus has been associated with learning and memory (Rissman E F., Sex with knockout models: behavioral studies of estrogen receptor alpha. Brain Res. 1999; 835(1):80-90). The secondary estrogen receptor type (ERβ), with poorly defined functions, is also present in the hippocampus, more so in humans than animal models (Shughrue P J, Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997; 388:507-525). ERα is not only present in inter-neurons but is also found at extra-nuclear sites on dendritic spines and astrocytes near spines, axons forming inhibitory and excitatory synapses. Astrocytes can regulate growth factors, synaptic remodeling and synaptic toss with aging (Zhao L, Estrogen receptor beta s a theraputic target for promoting neurogenesis and preventing neurodegeneration. Drug Dev Res. 2006; 66:103-117). Thus white matter abnormalities may be important in understanding sex differences in vulnerability to memory dysfunction with age, given the role of estrogenic signaling. Androgen receptors (ARs) are also found in the hippocampus but their role has been investigated less but are likely important in promoting an estrogen:androgen balance in neuronal function similar to what is observed in the breast (Toth-Fejel S, Estrogen and androgen receptors as comediators of breast cancer cell proliferation: providing a new therapeutic tool, Arch. Surg. 2004, 139: 50-54; Yeh S, Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor, J. Exp. Med. 2003, 198: 1899-1908; Agoff S N, Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohisto-chemical, clinical, and prognostic associations, Am. J. Clin. Pathol. 2003, 120: 725-731; Dorgan J F, Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17 beta-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 1997, 6: 177-81). Recent work has mapped the prefronatal cortex and anterior cingulate gyrus (ACG) in animal models to show that androgen receptors are in pyramidal and estrogens receptors are in the non-pyramidal cortical neurons (Garcia-Segura L M, Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair. Neuroscience. 1999; 89:567-578) with androgen receptors showing associations with excitatory projections and estrogen receptors associated with local inhibitory cortical cells. Thus, estrogen and androgen may have opposing influences on the cortex and neurotransmitter physiology (Kritzer M. The distribution of immunoreactivity for intracellular androgen receptors in the cerebral cortex of hormonally intact adult male and female rats: localization in pyramidal neurons making corticocortical connections. Cereb Cortex. 2004; 14(3):268-280). Together, this literature suggests important roles for both ERs and ARs in regulating dendritic formation and remodeling and underscores the importance of sex steroid-dependent brain developmental or adult function. More importantly, it suggests that a balance of estrogenic and androgenic inputs may be required for maintaining normal brain function.
Three important findings provide the basis for rethinking the current dogma and unifying our understanding of steroid-dependent deficits in mid-aged women. First of all, it is irrevocably clear that the profound deterioration in cognition in women is linked to the declining ovarian function that all women experience. It is unexplained however how the same decline in ovarian function observed for all women can contribute to such a diverse phenotype with some women severely compromised and others virtually unaffected. It is also abundantly clear that this deterioration in brain function precedes any detectable decline in the production of ovarian steroids but is closely associated with subtle changes that allow follicle stimulating hormone to rise. However, despite this “disconnect” between ovarian steroid hormone production and the onset of neural function decline, intervention with the primary ovarian steroid estradiol (or its congeners) ameliorates and even reverses the functional and behavioral decline that some women experience.
In summary, the efficacy of estrogen treatment indicates that a mechanism at the level of the neuron downstream of the estrogen receptor-signaling process is most likely the “final step” in maintaining optimal neural integrity. However, neither the circulating levels of women requiring estrogen therapy not the adverse systemic responses to exogenous estrogens support the concept that estrogen therapy represents anything similar to an “upstream” physiologic “replacement”. Thus the paradox has been that the process of cognitive loss is “caused” by change in ovarian function, as shown by the temporal relationship, and while estrogen treatment is an effective intervention it is clearly not a physiological treatment. So, what else occurs that: 1) parallels the time course of early ovarian function decline, 2) does not have the same qualities in all women, 3) will provide the same intracellular mechanism as estrogens can provide and 4) may explain why higher endogenous levels of DHEA may be beneficial while DHEA intervention has little benefit.
The first of these requirements is met by an observed increase in delta five steroids that occurs at the same trajectory as the phenotypic changes associated with the menopausal transition. The second requirement is met by the observation that while probably all women experience this rise in delta-5 steroids, the individuality of this endocrine event is sufficient to explain woman-to-woman differences in response, phenotype and health outcome. The third and fourth requirements are met by the observation that one of the delta 5 steroids (androstenediol) that are increased during the menopausal transition has both androgenic as well as estrogenic bioactivities. In fact, the observation that higher levels of the delta 5 steroid DHEA are protective for cognition loss, supports the concept that neural integrity is somehow related to this group of adrenal steroid hormones but not necessarily DHEA itself as interventions with this compound alone has had limited success. In sum, the recent recognition of these four aspects of the menopausal transition provides that basis for formulating a new approach to hormone replacement therapy. The present invention provides an approach that is based on the physiological changes that have been shown to occur in mid-aged women and one that fulfills the pharmacologic requirements of “estrogen replacement” indicated by years of intervention and experimentation.